Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[CH2:14][F:15])C1C=CC=CC=1.C([N:23]1[CH2:29][CH:28]([F:30])[CH2:27][O:26][CH2:25][CH2:24]1)C1C=CC=CC=1>CO.[C].[Pd]>[F:15][CH2:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][NH:8]1.[F:30][CH:28]1[CH2:27][O:26][CH2:25][CH2:24][NH:23][CH2:29]1
Reactant: FC1COCCN(Cc2ccccc2)C1
Reactant: FC[C@H]1COCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: FC1CNCCOC1
Product: FC[C@H]1COCCN1
Reaction time: 1 h

Procedure:
The crude mixture (2.2 g) obtained by the previous procedure, which contained mainly (3R)-4-benzyl-3-fluoromethylmorpholine and 4-benzyl-6-fluoroperhydro-1,4-oxazepine, was dissolved in methanol (50 ml). The solution was hydrogenated in the presence of 10% palladium-carbon (200 mg) at room temperature. After 1 hour of stirring, palladium-carbon was removed by filtration and the filtrate was evaporated under reduced pressure. The two isomers were separated by column chromatography using 2% of methanol in dichloromethane as an eluent to give (3R)-3-fluoromethylmorpholine and 6-fluoroperhydro-1,4-oxazepine (the former was less polar). The products were converted to their hydrochloride as a conventional manner using 4N hydrogen chloride in ethyl acetate, respectively.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCCNc1cnccn1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCCNc1cnccn1)c1ccccc1

Procedure:
Reacting 2-(3-aminopropylamino)pyrazine with benzoyl isothiocyanate by the procedure of Example 46 gives N-benzoyl-N'-[3-(2-pyrazinylamino)propyl]thiourea. Removing the benzoyl group by the procedure of Example 46 gives N-[3-(2pyrazinylamino)propyl]thiourea.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O[CH2:35][CH2:36][CH2:37][C:38]([CH3:52])([CH3:51])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=[O:40]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]([NH:26][C@H:27]([C:31]([O:33][CH2:35][CH2:36][CH2:37][C:38]([CH3:51])([CH3:52])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=[O:40])=[O:32])[CH:28]([CH3:29])[CH3:30])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COc1ccc(COC(=O)C(C)(C)CCCO)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)(C)CCCOC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a mixture of DCC (9.41 g, 46 mmol), DMAP (0.586 g, 4.8 mmol) and N-CBz-L-valine (12.1 g, 48 mmol) in CH2Cl2 (200 mL) at 0° C., was added dropwise a solution of 4-methoxybenzyl 5-hydroxy-2,2-dimethyl-valerate (6.40 g, 24 mmol) in CH2Cl2 (50 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 1→4% MeOH in CH2Cl2), to give 8.61 g 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[C:15]3[CH2:26][C:18]4[NH:19][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[C:17]=4[C:16]3=[O:27])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(CC2CCN(CC3C=CC=CC=3)CC2)CN2C3C=CC(OC)=CC=3C=C2C1=O>C(OCC)(=O)C.C(O)C>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH:15]3[CH2:26][C:18]4[NH:19][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[C:17]=4[C:16]3=[O:27])[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=CC2CCN(Cc3ccccc3)CC2)Cc2[nH]c3ccccc3c21
Agent: COc1ccc2c(c1)cc1n2CC(C)(CC2CCN(Cc3ccccc3)CC2)C1=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1c2c([nH]c3ccccc23)CC1CC1CCN(Cc2ccccc2)CC1

Procedure:
the title compound of Example 42 (176 mg, 0.5 mmol) was dissolved in a mixture solvents of ethyl acetate (31 ml) and ethanol (31 ml) and treated with PtO 2 (23 mg) and hydrogenated at 35 psi at r.t. for 2 hours. The mixture was filtered through diatomaceous earth (Celite (trademark)) and the filtrate was concentrated to give compound the title compound as off-white solid. 1HNMR (CDCl3)δ 1.3-1.65 (m, 4H), 1.65-1.8 (m, 2H), 1.9-2.1 (m, 3H), 2.65 (dd, 1H), 2.9-3.1 (m, 3H), 3.2 (dd, 1H), 3.55 (s, 2H), 7.15-7.4 (m, 8H), 7.9 (dd, 1H), 9.15 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([S:6]([C:9]1[N:13]=[CH:12][NH:11][N:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18](Cl)=[O:19])[CH:15]=[CH2:16].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18]([N:11]1[CH:12]=[N:13][C:9]([S:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[N:10]1)=[O:19])[CH:15]=[CH2:16]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCCCS(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCCCC)n1

Procedure:
A mixture of 10.2 g. 3-pentylsulphonyl-1,2,4-triazole, 8.2 g. diallylcarbamoyl chloride, 75 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride. An oily residue was obtained which was distilled under reduced pressure to give a product, b.p. 193° - 194° C./0.25 mm., which solidified on cooling. This product was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-diallylcarbamoyl-3-n-pentylsulphonyl-1,2,4-triazole, m.p. 28° - 30° C. Elemental analysis satisfactory.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]3[C:12]([NH:13][C:14](=[O:24])[CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:16]3)=[CH:11][C:10]=2[Cl:25])[CH:5]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=1)=[C:34]=[O:35].O>CN(C)C=O>[Cl:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:34]([NH:33][C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:45][CH:46]=3)=[O:35])=[CH:5]1)[N:16]=[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](=[O:24])[NH:13]2
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: CCOC(=O)C1Nc2cc(-n3ccc(CN)c3)c(Cl)cc2NC1=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)NCc2ccn(-c3cc4nc(C(=O)OCC)c(=O)[nH]c4cc3Cl)c2)cc1
Reaction time: 3 h
Yield: 31.6 %

Procedure:
To a solution of the compound of Example 5 (61.2 mg, 159 μmol) in N,N-dimethylformamide (1.6 ml) were added triethylamine (33.3 μl, 239 μmol) and successively ethyl 4-isocyanatobenzoate (36.5 mg, 191 μmol) at room temperature, and the mixture was stirred for 3 hours at the same temperature. Water was added to the reaction mixture and the precipitated crystals were collected by filtration. After washed with water and then with ethyl acetate, these were air-dried, thereby obtaining 27.0 mg of title compound as yellowish brown powder. Yield 32%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].N1CCCCC1.O>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1cccc(/C=C/N(C)C)c1[N+](=O)[O-]

Procedure:
A solution of methyl 3-methyl-2-nitrobenzoate (43 g, 0.22 mole), dimethylformamide dimethyl acetal (52.5 g, 0.44 mole) and piperidine (18.7 g, 0.22 mole) in dimethylformamide (120 ml) was heated under reflux for 24 hours, cooled and poured into water to give the crude product.
Reaction SMILES: C([O:3][C:4]1[N:9]=[N:8][C:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)=[C:6]([C:31]([F:34])([F:33])[F:32])[CH:5]=1)C.[BrH:35].CC(O)=O>>[F:34][C:31]([F:32])([F:33])[C:6]1[CH:5]=[C:4]([OH:3])[N:9]=[N:8][C:7]=1[C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[N:17][CH:16]=[CH:15][C:14]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][N:22]=2)[N:19]=1.[BrH:35]
Reactant: CCOc1cc(C(F)(F)F)c(-c2ccc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)nn1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)c(-c2ccc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolve 7-[6-ethoxy-4-(trifluoromethyl)pyridazin-3-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-1,8-naphthyridin-4-amine (560 mg, 1.16 mmol) in HBr/AcOH (33% wt; 10 mL) and stir for 4 hours at room temperature. Remove the solvent under reduced pressure. Add toluene (25 mL) and remove the solvent under reduced pressure. Dry under vacuum to yield the title compound as its HBr salt (618 mg, 100%). LC/MS (MH+) 453.97.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9](C(O)C(CCO)CC3C=C(OC)C=CC=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.[CH2:38]([N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[CH3:39].[CH2:45]1[CH2:49][O:48][CH2:47][CH2:46]1>C(OCC)(=O)C>[CH2:38]([N:40]1[CH2:43][CH2:44][CH:42]([CH2:17][C:12]2[CH:13]=[CH:46][CH:45]=[C:49]([O:48][CH3:47])[CH:11]=2)[CH:41]1[C:9]1[O:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[C:39]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: COc1cccc(CC(CCO)C(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: COc1cccc(CC2CCN(Cc3ccccc3)C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[3-(4,5-diphenyloxazol-2-yl)-3-hydroxy-2-(2-hydroxyethyl)propyl]-1-methoxybenzene (3.3 g) and methanesulfonyl chloride (1.8 ml) and triethylamine (4.3 ml) in THF (50 ml) was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate and washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The residue was dissolved in benzylamine (10 ml). After being stirred for 2 hours at 80° C., the mixture was partitioned between ether and water. The organic layer was washed with water and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to afford 1-benzyl-2-(4,5-diphenyloxazol-2-yl)-3-(3-methoxybenzyl)pyrrolidine (1.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1.Br[C:22]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:23]=2[CH:24]=[O:25])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: COC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O[CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C1(C)C(C)=CC=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCO
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A mixture of 30.6 g (0.11 mole) 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 32.6 g (0.1 mole) N-(2-hydroxyethyl)stearamide, 0.8 g Tyzor TBT, and 100 ml xylene was refluxed for six hours. The water (1.8 ml) was trapped in a Stark & Dean trap. The solution was filtered through Microcel (trademark, synthetic calcium silicate) and the solvent was removed by vacuum stripping. The title compound (51 g) was recrystallized from acrylonitrile. It melted at 52°-55° C.
Reaction SMILES: [CH2:1]([N:8]=[C:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:17][C:16]=2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CO.[BH4-].[Na+]>C(OCC)C.[OH-].[Na+]>[CH2:1]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:23])[CH3:24])=[CH:17][C:16]=2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 17 h

Procedure:
To a flask equipped with magnetic stirrer was added N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]amine (4.00 g, 7.63 mmol) and tetrahydrofuran (480 ml) followed by methanol (120 ml). To the solution was added sodium borohydride (1.16 g, 30.5 mmol) and the reaction mixture stirred for 17 hr. The reaction mixture was then diluted with diethyl ether (600 ml) and aqueous sodium hydroxide (400 ml, 0.4M) was added. After stirring for 10 min, the layers were separated and the aqueous layer extracted with dichloromethane (3×100 ml). The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. Purification via FCC (SiO2, ethyl acetate/petroleum ether, gradient elution using 1:9, 1:4, then 3:7, v/v) furnished the title compound as a cream solid (2.09 g, 54%). δH (CDCl3) 0.01 (6H, s), 0.05 (6H, s), 0.80 (9H, s), 0.85 (9H, s), 1.18 (4H, m), 1.66 (2H, m), 1.87 (2H, m), 2.19 (1H, m), 2.68 (1H, M), 6.12 (1H, d), 6.23 (1H, dd), 6.77 (1H, d), 7.17 (5H, m).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:21]4[N:22]=[C:23]([C:25]5[CH:26]=[N+:27]([O-])[CH:28]=[CH:29][CH:30]=5)[N:24]=[C:20]4[N:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:28]1[N:27]=[CH:26][C:25]([C:23]2[N:24]=[C:20]3[N:19]=[CH:18][CH:17]=[C:16]([C:8]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:15])[F:14])=[C:6]([O:5][CH2:4][CH:1]5[CH2:3][CH2:2]5)[CH:7]=4)[N:21]3[N:22]=2)=[CH:30][CH:29]=1.[Cl:34][C:26]1[C:25]([C:23]2[N:24]=[C:20]3[N:19]=[CH:18][CH:17]=[C:16]([C:8]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:15])[F:14])=[C:6]([O:5][CH2:4][CH:1]5[CH2:3][CH2:2]5)[CH:7]=4)[N:21]3[N:22]=2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc(-c2nc3nccc(-c4ccc(OC(F)F)c(OCC5CC5)c4)n3n2)c1
Product: FC(F)Oc1ccc(-c2ccnc3nc(-c4ccc(Cl)nc4)nn23)cc1OCC1CC1
Product: FC(F)Oc1ccc(-c2ccnc3nc(-c4cccnc4Cl)nn23)cc1OCC1CC1
Yield: 38 %
Yield: 30 %

Procedure:
In POCl3, dissolved was 3-[7-{3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl}-[1,2,4]triazolo[1,5-a]pyri midine-2-yl]-pyridine-N-oxide (Compound 102) (2.7 g, 6.347 mmol), and the mixture was heated under reflux. The solvent was distilled under reduced pressure, and NaHCO3(aq.) was added to the residue. The mixture was extracted three times with EA, and the extract was washed twice with brine, dried over MgSO4, filtered and evaporated under reduced pressure to remove solvent. The mixture was purified via silica gel column chromatography (hexane/EA, 1/1) to obtain the desired compound, 2-(6-chloropyridin-3-yl)-7-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidine (Compound 104) (0.07 g, 30%) and 2-(2-chloropyridin-3-yl)-7-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidine (Compound 105) (0.09 g, 38%).
Reaction SMILES: ClC(C)C(C1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=CC=1)=O.[CH3:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=1.C(=O)([O-])[O-:41].[Na+].[Na+]>C(O)C>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([CH:9]([CH3:10])[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:16]=3)=[O:41])[CH2:34][CH2:33]2)=[CH:38][CH:39]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: CC(Cl)C(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CC2CCN(C(C)C(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
13.7 g (0.05 mol) of 2-chloro-4'-(4-benzyloxyphenyl)-propiophenone are added to a solution of 9.4 g (0.05 mol) of 4-(4-methylbenzyl)-piperidine in 50 ml of ethanol, 5.3 g (0.05 mol) of sodium carbonate are then added and the mixture is heated under reflux for 3 and a half hours and left to stand overnight. The inorganic precipitate is filtered off, the ethanol is evaporated off, the oily residue is taken up in acetone and the acetone is evaporated off. The residual oil is chromatographed on 80 g of silica using acetone as the eluant, and 21 g of an oil used as such in the subsequent reduction, are collected.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[CH:6]=[CH:5]1>CO.O>[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]=[CH:5]1
Reactant: CC1(C)C=CC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)C=CC(O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
Sodium borohydride (5.03 g, 133 mmol) was added portion-wise to a stirred solution of 4,4-dimethylcyclohex-2-enone (15.0 g, 121 mmol) in methanol (403 mL) in a water bath. Once addition was complete, the solution was allowed to stir under a nitrogen atmosphere at room temperature for 3 h. The reaction mixture was diluted with water (150 mL) and the majority of the methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (2×200 mL). The combine ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil under reduced pressure to afford 4,4-dimethylcyclohex-2-enol (13.4 g, 106 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.41-5.57 (m, 1H), 5.24-5.42 (m, 1H), 4.61 (d, J=5.47 Hz, 1H), 3.82-3.99 (m, 1H), 1.65-1.83 (m, 1H), 1.21-1.59 (m, 3H), 0.93 (d, J=15.23 Hz, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[CH:17]=[O:18])[CH:20]=1
Reactant: OB(O)c1cccnc1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 95 °C
Yield: 47 %

Procedure:
5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) (1.53 g, 4.30 mmol), pyridine-3-boronic acid (CXXXI) (0.58 g, 4.73 mmol), and potassium phosphate tribasic (1.37 g, 6.45 mmol) was dissolved in 1,4-dioxane (43.0 mL) and water (9.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.4301 mmol) was added, and the reaction was heated to 95° C. for 2.5 h. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic phase was separated and washed sequentially with water and brine. The material was dried (MgSO4), concentrated, and purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes→1:1 EtOAc:hexanes) to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.62 g, 2.02 mmol, 47% yield) as a tan amorphous solid. 1H NMR (DMSO-d6) δ ppm 10.23 (s, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.61 (dd, J=4.8, 1.5 Hz, 1H), 8.39 (d, J=0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.95-7.93 (m, 1H), 7.64-7.60 (m, 1H), 6.13 (dd, J=9.4, 2.4 Hz, 1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45-2.41 (m, 1H), 2.11-2.07 (m, 2H), 1.82-1.78 (m, 1H), 1.66-1.62 (m, 2H); ESIMS found for C13H17N3O2 m/z 308 (M+H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CC2)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), cyclopropylboronic acid (78.5 mg, 0.914 mmol), saturated aqueous sodium carbonate solution (3 ml), and tetrakis(triphenylphosphine)palladium(0) (19.0 mg, 0.0172 mmol) in dimethoxyethane (5 ml) was stirred at 90° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (70.0 mg, 39.8%) as an oil.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:12][CH:11]=1.[I:22]I>C1COCC1>[I:22][C:20]1[S:19][CH:18]=[C:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH:21]=1
Reactant: Fc1ccc(Cc2ccsc2)cc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2csc(I)c2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 87.6 %

Procedure:
To a solution of LDA (3.67 mmol) in THF at -78° C. was added a solution of 3-(4-fluorophenylmethyl)thiophene (640 rag, 3.33 mmol), prepared as in Example 35, step 1, and the reaction mixture was stirred for 25 min. A solution of I2 (1.01 g, 4.00 mmol) in THF was added and the cold bath was removed. The reaction mixture was warmed to ambient temperature, quenched with saturated aqueous NH4Cl, and extracted with ether. The organic phase was washed with 1N aqueous H3PO4, saturated aqueous NaHCO3, saturated aqueous Na2S2O3, and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 928 mg of 2-iodo-4-(4-fluorophenylmethyl)thiophene which was used without further purification.